This proposal requests continued funding for our Center of Biomedical Research Excellence (COBRE) on 'Mechanisms of Cardiovascular Remodeling." The original COBRE grant enabled our fledgling Cardiovascular Research Institute (CRI) at the Sanford School of Medicine (SSOM, formerly University of South Dakota School of Medicine) to develop a national reputation for research excellence in the area of heart failure. COBRE funding facilitated the career development of promising junior basic researchers and promoted research training for clinician scientists. Funding enabled us to improve research efficiency with the establishment of excellent core facilities and to recruit outstanding new junior and senior level faculty members. These developments resulted in a significant number of publications with many in prestigious medical journals and enabled the establishment of excellent new seminar and journal club programs on our clinical campus in Sioux Falls. This highly successful COBRE also served as a major catalyst for research investment and expansion at the local (new $20M research investment pledge by our partner hospital, development of 4 more research institutes in Sioux Falls) and State level (State 2010 Program and establishment of MD-PhD program at SSOM). In our competing renewal application, we are requesting continued support of the infrastructure established by the original COBRE and project funding for 5 promising investigators (4 junior and one mid level). Project 1 by Dr. Tim O'Connell will investigate the role of alpha adrenergic receptors in myocardial infarction. Project 2 by Dr. Stephen Armstrong will investigate molecular mechanisms of integrin signaling in dilated cardiomyopathy and muscular dystrophy. Project 3 by Dr. Qiangrong Liang will investigate the molecular mechanism of cardiac toxicity from the anti-cancer drug Doxorubicin. Project 4 by Erin Harmon will investigate the role of a myotonic dystrophy kinase in myocyte development. Project 5 by David Wang will investigate the molecular mechanisms of thyroid hormone induced angiogenesis in adult heart. Projects are dependent on the Administrative, Physiology, Cell Culture, Molecular Biology, and Imaging Cores provided by the COBRE. Relevance-Work being conducted in this COBRE grant involves investigations into the cellular and molecular mechanisms of cardiovascular remodeling associated with heart development, growth, and disease. The COBRE has also enabled the establishment of a highly focused and productive group of scientists who have established a national reputation for excellence in cardiovascular research in a State that has historically ranked near the bottom in research productivity.